It is well recognized that there is a genetic component conferring risk for developing atopy and asthma. Linkage studies of human populations throughout the world have identified a large number of regions associated with these diseases. Candidate genes and polymorphisms within these regions have been associated with atopy and asthma. However, identifying a causative role for these alleles in the pathogenesis of these polygenic disorder(s) has proven difficult. The overall goal of this proposal is to develop mouse lines for testing causality of human genetic variants in functional screens of allergic airway disease. Specifically, we will test the hypothesis that individual substitution polymorphisms in genes of the IL13/IL4 pathways associated with atopy and asthma in various human populations are causative, altering the function of the protein in a manner that contributes to the development of allergic disease. We will also test the hypothesis that there is gene-gene interaction in atopy and asthma and that synergy between these disease associated alleles of the IL13/IL4 pathway further increases risk for disease. To test these hypotheses, we develop a novel panel of mouse lines which allows the consequence of inheritance of atopy associated IL13 and IL4R1 alleles to be evaluated both in primary cells ex vivo and during development of allergic lung disease in the mouse. PUBLIC HEALTH RELEVANCE. Asthma remains a major cause of morbidity in the US, with an enormous impact on health care costs and the economy. Particularly troubling is the lack of new treatments for this disease. The NIH has sponsored a large number of clinical trials investigating the genetics of asthma, and a number of candidate loci have been identified. However, there is no in vivo experimental data confirming the importance of these loci in the pathophysiology of asthma. This application plans to evaluate asthma candidate genes in the mouse, using genetic approaches.